In the first funding period of this project, it was demonstrated that genetic factors have a major role in the development of Alzheimer's disease (AD). Recent studies have shown an association between the E4 isoform of apolipoprotein E (ApoE) and risk of AD. Despite the overwhelming evidence supporting a role for E4 as a major risk factor for AD, this marker has only modest sensitivity and specificity. The primary objective of this proposal is to evaluate the association between polymorphisms for ApoE, other genetic and non-genetic risk factors, and susceptibility to AD. In order to carry out this project successfully, a total sample of 2000 patients meeting NINCDS/ADRDA criteria for probable or definite AD from 10 research centers participating in the national genetic epidemiological study of AD (MIRAGE) will be collected. Family history, medical history, and epidemiological information from AD probands and their first degree relatives will be collected using standardized questionnaire instruments and established protocols. A cognitive screening test will be administered by telephone to all living first-degree relatives. Individuals who appear to be cognitively impaired will be screened more intensively to determine their dementia status. The probability that each AD patient has a major gene form of the disorder (MGAD) will be calculated using statistical genetic techniques. DNA samples will be obtained for all living subjects and genotyped for ApoE. Fasting cholesterol levels will be determined in all living unaffected subjects. The proportion of genetic variability in AD susceptibility accounted for by ApoE will be estimated, and likely genetic models for other common AD susceptibility will be fit by segregation analysis and other statistical techniques that adjust for the MGAD probability. Models of gene-environment interaction on risk and age at onset of AD will be evaluated by joint analysis of ApoE genotypes with the MGAD probability scores and non-Mendelian risk factors, such as smoking, education level and exposure to anti-inflammatory drugs. Factors that enable an individual to survive to age 90 without succumbing to AD will be identified. Relationships among cognitive performance, ApoE genotype, MGAD probability, and total cholesterol level among non-demented relatives will be examined. The investigators state that success in this project will help identify the combination of genetic and non-genetic factors yielding the highest susceptibility to AD, and hence suggest clues for better treating or preventing the disorder. They further state that this study may suggest efficacious strategies for future laboratory studies to elucidate pathogenic mechanisms of AD and that this registry will also provide the resources and baseline data for AD gene mapping projects and prospective epidemiological studies of AD among individuals with heightened risk.